Project Summary and Relevance Human respiratory syncytial virus (RSV) is a major cause of serious lower respiratory tract infections and hospitalization in infants, the elderly and immunocompromised individuals. Natural infection does not induce durable protective immunity to the virus and multiple reinfections can occur even within the same year. To date, there is as yet no effective vaccine or treatment. We have developed novel RSV-virus-like particle (VLP) vaccine candidates composed of Newcastle Disease Virus nucleoprotein and membrane proteins that express RSV F and G glycoproteins ectodomains fused with NDV glycoprotein cytoplasmic domains. This VLP induces long-lived protective neutralizing antibody responses and memory B cells in mice when given once in the absence of adjuvant. Mice challenged with RSV post immunization clear the virus and do not display enhanced pulmonary disease. Because adjuvant is not required for this protective immune response, we propose that the VLP directly stimulates the innate immune system, such as TLRs or MAV. We will investigate this possibility by using mutant mouse models deficient in single components of the innate immune system and the impact on development of durable protective immunity. These studies will provide essential information for the future development of our vaccine candidate and define the most efficacious TLR agonists for clinical testing